The objective of this grant is to study tumor progression from hormone dependency to autonomy, using the Dunning R3327 rat prostate adenocarcinoma as a model. It is well known that human prostatic cancer, while initially hormone-dependent, eventually relapses to an androgen-insensitive state and it is the goal of our studies to elucidate those factors that control tumor progression and thus ultimately to design treatment protocols that will minimize the emergence of new cell types. Towrads this goal, the following specific aims will be pursued. (1) The mechanism of selection and/or adaptation during relapse from androgen dependence to androgen insensitivity will be studied using rats that have undergone various types of hormonal treatment or chemotherapy, and in rats whose immune system has been altered. The goal of these studies is to better understand those factors that affect tumor progression, so that more effective and rational therapies for the initial treatment of prostate cancer can be designed. (2) Subpopulations of cells will be isolated from the R3327 prostate tumor and characterized in terms of hormone-dependence and sensitivity, steroid receptor content, growth rate in vivo, DNA content, and histology. These studies are being done to gain a better understanding of the types of cells that co-exist within a tumor. (3) Interactions between various cell populations will be studied in rats inoculated with more than one cell type, in order to determine whether a particular cell population can alter the growth rate, genetic stability, or metastatic capacity of other cell populations. Such studies are of importance in the design of chemotherapeutic protocols that will minimize the emergence of new cell types with altered hormone-dependence, growth rate or metastatic capacity and thus provide a more effective treatment for human prostatic cancer.